Genetic modifiers of mammary tumor susceptibility

乳腺肿瘤易感性的遗传修饰

• 批准号: 7740940
• 负责人: D. Joseph Jerry
• 金额: $ 6.53万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-15 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7740940
• 关键词: Alleles; Biological Markers; Cancer Patient; Cell Line; Chromosomes, Human, Pair 7; Common Neoplasm; Complex; Computer Simulation; Congenic Mice; DMBT1 gene; DNA Double Strand Break; Disease; Dissection; Double Strand Break Repair; Epithelial Cells; Exhibits; Genes; Genetic; Genetic Recombination; Haplotypes; Human; Inbred BALB C Mice; Incidence; Individual; Inherited; Li-Fraumeni Syndrome; Location; Loss of Heterozygosity; Mammary Gland Parenchyma; Mammary Neoplasms; Mammary gland; Maps; Mediating; Monitor; Mus; Mutation; Neoplasm Transplantation; Pathway interactions; Predisposition; Procedures; Research Personnel; Resistance; Risk; Staging; TP53 gene; Therapeutic Intervention; Tumor Suppressor Genes; Tumor Suppressor Proteins; Woman; base; glycoprotein 340; homologous recombination; malignant breast neoplasm; mouse model; programs; repaired; resistance allele; trait; tumor; tumor progression

Breast cancer is a complex disease with both environmental and genetic factors contributing to an individual's risk of developing disease. Heritable mutations in TP53 have been associated with Li-Fraumeni syndrome in which breast cancer is the most common tumor. Mouse models of Li-Fraumeni syndrome also exhibit frequent mammary tumors, butdepends onthe geneticbackground. The differencein incidenceof mammarytumors betweenBM-Blc-Trp53*'~ mice (susceptible) and C57BU6-Trp5y'~ mice (resistant) has allowed us to investigate genetic mechanisms that modify susceptibility to mammarytumors. We havedemonstrated that bothrecessive-acting anddominant-acting susceptibility alleles contribute to mammary tumor susceptibility. A recessive-acting locus that acts as a suppressor of mammary tumors (SuprMaml) has been mapped to a 10 Mb region of mouse chromosome 7. In contrast, a recombination pathway mediated loss of heterozygosity at Trp53 inmammarytumors andwas inherited as adominant trait. Therefore, BALB/c alleles appear to interferewith rates or fidelity of homology-directed repair of DMA double strand breaks. These observations provide a means to identify genes and pathwaysthat influence susceptibility to mammary tumors in mice. SpecificAim 1:Analysis of the effect of Dmbtlinsuppression of mammarytumors.Aim1.1: The effects ofDmbtl as a tumor suppressor gene will be examined. Expression constructs will be introduced into mammary epithelial cell lines andchanges intumor incidence will bemonitored. Aim 1.2: Expressionof DMBT1 protein innormal human breast tissues and tumors will be determined to assess the value of DMBT1 as a biomarker. Specific Aim 2: Genetic dissection of the effects ofthe SuprMaml locus on incidence of mammary tumors. Aim 2.1: The magnitude of the tumor suppressive effect of the SuprMaml locus on incidence of mammary tumors will be determined using in congenic mice. Aim 2.2: The interval will be subdivided in separate congenic mice to refine the location of the tumor suppressor activity. Specific Aim 3: Analysis of dominant-acting modifiers that alter rates of repair of DNA double strand breaks. Genetic background may influence susceptibility to mammarytumors byaltering the rates or fidelity of DNArepair. Therefore, rates of DNA double strand break repair will be monitored using synthetic substrates. Identificationofgenes thatmodifysusceptibilitytomammarytumors willprovidemarkers for riskassessment andnovel targets for therapeutic intervention.

乳腺癌是一种复杂的疾病，环境和遗传因素都对个体的风险有影响

项目成果

Virus-inspired approach to nonviral gene delivery vehicles.

• DOI: 10.1021/bm900370p
• 发表时间: 2009-08-10
• 期刊: Biomacromolecules
• 影响因子: 6.2
• 作者: Roy R;Jerry DJ;Thayumanavan S
• 通讯作者: Thayumanavan S

Pathways contributing to development of spontaneous mammary tumors in BALB/c-Trp53+/- mice.

有助于 BALB/c-Trp53/- 小鼠自发性乳腺肿瘤发生的途径。

• DOI: 10.2353/ajpath.2010.090438
• 发表时间: 2010
• 期刊: The American journal of pathology
• 作者: Yan,Haoheng;Blackburn,AnnekeC;McLary,SChristine;Tao,Luwei;Roberts,AmyL;Xavier,ElizabethA;Dickinson,EllenS;Seo,JaeHong;Arenas,RichardB;Otis,ChristopherN;Cao,QingJ;Lawlor,RebeccaG;Osborne,BarbaraA;Kittrell,FrancesS;Me
• 通讯作者: Me

Regulation of cancer stem cells by p53.

p53 对癌症干细胞的调节。

• DOI: 10.1186/bcr2133
• 发表时间: 2008
• 期刊: Breast cancer research : BCR
• 作者: Jerry,DJoseph;Tao,Luwei;Yan,Haoheng
• 通讯作者: Yan,Haoheng

siRNA screening identifies differences in the Fanconi anemia pathway in BALB/c-Trp53+/- with susceptibility versus C57BL/6-Trp53+/- mice with resistance to mammary tumors.

• DOI: 10.1038/onc.2013.38
• 发表时间: 2013-11-28
• 期刊: Oncogene
• 影响因子: 8

Map making in the 21st century: charting breast cancer susceptibility pathways in rodent models.

• DOI: 10.1007/s10911-011-9201-9
• 发表时间: 2011-04
• 期刊: Journal of mammary gland biology and neoplasia
• 影响因子: 2.5
• 作者: Blackburn AC;Jerry DJ
• 通讯作者: Jerry DJ